Subtype-specific secretomic characterization of pulmonary neuroendocrine tumor cells

Xu Dong Wang, Rongkuan Hu, Qing Ding, Trisha K. Savage, Kenneth E. Huffman, Noelle S Williams, Melanie H Cobb, John D Minna, Jane E Johnson, Yonghao Yu

Research output: Contribution to journalArticle

Abstract

Pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC), is a particularly aggressive malignancy. The lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1 and POU2F3 have been reported to identify the different subtypes of pulmonary NE cancers. Using a large-scale mass spectrometric approach, here we perform quantitative secretome analysis in 13 cell lines that signify the different NE lung cancer subtypes. We quantify 1,626 proteins and identify IGFBP5 as a secreted marker for ASCL1High SCLC. ASCL1 binds to the E-box elements in IGFBP5 and directly regulates its transcription. Knockdown of ASCL1 decreases IGFBP5 expression, which, in turn, leads to hyperactivation of IGF-1R signaling. Pharmacological co-targeting of ASCL1 and IGF-1R results in markedly synergistic effects in ASCL1High SCLC in vitro and in mouse models. We expect that this secretome resource will provide the foundation for future mechanistic and biomarker discovery studies, helping to delineate the molecular underpinnings of pulmonary NE tumors.

Original languageEnglish (US)
Article number3201
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

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Neuroendocrine Cells
Neuroendocrine Tumors
Small Cell Lung Carcinoma
Tumors
Lung Neoplasms
tumors
cancer
Cells
E-Box Elements
Lung
lungs
Biomarkers
Transcription
Insulin-Like Growth Factor I
Transcription Factors
Chemical analysis
Pharmacology
Cell Line
Proteins
biomarkers

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Subtype-specific secretomic characterization of pulmonary neuroendocrine tumor cells. / Wang, Xu Dong; Hu, Rongkuan; Ding, Qing; Savage, Trisha K.; Huffman, Kenneth E.; Williams, Noelle S; Cobb, Melanie H; Minna, John D; Johnson, Jane E; Yu, Yonghao.

In: Nature communications, Vol. 10, No. 1, 3201, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Hu, Rongkuan

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AU - Savage, Trisha K.

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AU - Williams, Noelle S

AU - Cobb, Melanie H

AU - Minna, John D

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